Epilepsia, 45(8):908–915, 2004 Blackwell Publishing, Inc. C  2004 International League Against Epilepsy Chromosomal Mapping of Genetic Loci Controlling Absence Epilepsy Phenotypes in the WAG/Rij Rat ∗ Dominique Gauguier, †Gilles van Luijtelaar, ∗ Marie Th´ er` ese Bihoreau, ∗ Steven P. Wilder, ∗ Richard F. Godfrey, †Jo Vossen, †Anton Coenen, and ‡Roger D. Cox ∗ The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, England; †NICI-Biological Psychology, Nijmegen University, Nijmegen, The Netherlands; and ‡Medical Research Council, Mammalian Genetics Unit, Harwell, Didcot, Oxfordshire, United Kingdom Summary: Purpose: The WAG/Rij rat is among the most appro- priate models for the study of spontaneous childhood absence epilepsy, without complex neurologic disorders that are asso- ciated with some mouse models for absence epilepsy. Previous studies have allowed the identification of distinct types of spike– wave discharges (SWDs) characterizing seizures in this strain. The purpose of this study was to investigate the genetic basis of electroencephalographic (EEG) properties of SWDs. Methods: An intercross was derived from WAG/Rij and ACI inbred strains that are known to differ substantially in the number of SWDs. Phenotypic analyses based on 23-h EEG recording in all progenies allowed the quantification of type I and type II SWD phenotypes. A genome-wide scan was performed with 145 microsatellite markers, which were used to test for evidence of genetic linkage to SWD quantitative phenotypes. Results: We were able to map quantitative trait loci inde- pendently, controlling type I and type II SWD variables to rat chromosomes 5 and 9. Strongest linkages were obtained for D5Mgh15 and total duration of type II SWD (lod, 3.64) and for D9Rat103 and the average duration of type I SWD (lod, 3.91). These loci were denoted T2swd/wag and T1swd/wag, respectively. Conclusions: The independent genetic control of type I and type II SWDs underlines the complexity of the molecular mecha- nisms participating in SWDs. The identification of these genetic loci represents an important step in our fundamental knowledge of the architecture of SWDs and may provide new insights for resolving the genetic heterogeneity of absence epilepsy. Key Words: Genetics—WAG/Rij rat—Quantitative trait locus— QTL—Absence epilepsy—Spike–wave discharges—SWDs. Idiopathic generalized epilepsy (IGE) is a group of complex disorders, which includes childhood absence epilepsy (CAE). The difference from other forms of ab- sence epilepsy such as juvenile absence epilepsy (JAE) is the age at onset and the frequency of occurrence. CAE is characterized by an early age at onset and up to several hundreds of attacks per day, whereas JAE starts around puberty with absences occurring less frequently than one per day. CAE or pyknolepsy is the archetypical epileptic syndrome of typical absence seizures (1). It is charac- terized by typical bilateral generalized spike–wave dis- charges (SWDs) on the EEG activity and a concomi- tant impairment of consciousness (absence). Absences are brief (2–5 s) or long (15–30 s) and have a sudden onset and termination. The background EEG activity is usually normal, although paroxysmal activity may occur (2). Es- timations of incidence range from 0.7 to 4.6 per 100,000 Accepted March 24, 2004. Address correspondence and reprint requests to Dr. R.D. Cox at MRC Mammalian Genetics Unit, Harwell, Didcot, Oxfordshire OX11 0RD, U.K. E-mail: r.cox@har.mrc.ac.uk Drs. Gauguier and van Luijtelaar contributed equally to this study. in the general population and from 6 to 8 per 100,000 in children and adolescents up to age 15 years (3). The proportion of patients with typical absences among peo- ple with epilepsy is ∼3%, and the prevalence of typical absences among children with epilepsies is ∼10% (1). Absences usually respond well to ethosuximide (ESM) or sodium valproate (VPA) and remit within 2–5 years from onset (2). Both the high concordance (>85%) of IGE in monozy- gotic twins and results from segregation studies support the existence of a strong genetic component in the eti- ology of this disease (4,5). Results from linkage and as- sociation studies in humans have demonstrated the ex- istence of multiple genes involved in various forms of the disease and highlighted the complexity of genetic in- vestigations in human epilepsy (6). Evidence of genetic linkage to human 8q24 was found in a particular type of CAE (evidence of absence epilepsy highly characteristic SWD plus tonic–clonic generalized seizures) and repli- cated in two independent studies (7,8). An association be- tween CAE and genetic variants in the γ -aminobutyric acid type A–receptor subunit β 3 (GABRB3) located on 908